Neural stem cells are mainly restricted to specific niches which in rodents are the subventricular zone (SVZ) in the lateral ventricles and the subgranular zone (SGZ) in the hippocampal dentate gyrus [Doetsch F, Caille I, Lim D A, et al., Cell. 1999; 97:703-716]. In the adults, type B cells express glial markers, have astrocyte characteristics, bundles of intermediate filaments and multiple processes and generate neuroblasts (type A cells, neuronal precursors) through a highly proliferative transit amplifying population (type C cells). The cell bodies of type B astrocytes are generally located under the ependymal layer of the lateral ventricles, have short processes that extend through it, with small apical endings on the ventricle, in addition to frequently tangentially oriented long basal processes with specialized end feet on blood vessels. Thus, adult SVZ B cells, similarly to the radial glia (RG) during development, retain an apical-basal polarity and are part of the ventricular epithelium. In fact, although the radial glia disappears postnatally by transformation into parenchymal astrocytes, some radial glial cells persist within the adult SVZ hidden among astrocytes of the glial tubes. This modified radial glia belongs to the astroglial lineage (type B cells) and maintains self-renewal potential and pluripotency, the two stem cell characteristics.
It is well documented the migration of adult neuroblasts in a pathway known as rostral migratory stream (RMS), in longitudinal clusters from their SVZ niche towards the olfactory bulb (OB), where dying neurons should be replaced. In addition, migration of cells from SVZ towards non-olfactory bulb regions in the adult has been reported on several disease or injury models [Arvidsson A, Collin T, Kirik D, et al., Nat Med. 2002; 8:963-970]. Surgical RMS disruption led to migration of BdrU+PSA-NCAM+ cells from the SVZ into the anterior olfactory nucleus, the frontal cortex and the striatum [Alonso G, Prieto M, Chauvet N., J Comp Neurol. 1999; 405:508-528]. In addition, in response to an induced brain tumor, the migration of endogenous neuroblasts towards the lesion site could be followed in vivo by magnetic resonance imaging (MRI) [Elvira G, Garcia I, Benito M, et al., PLoS One. 2012; 7:e44466].
Although DCX+ neuroblasts are thought to be the major migratory SVZ cells, type C cells might migrate as well. Many of the migration experiments have been done using BrdU-labeled cells, where some, but not all the labeled cells were neuroblasts. Indeed, several reports suggest that other precursor cells from the SVZ are able to migrate towards a brain lesion site. For instance, on transgenic mice expressing a nestin driven green fluorescent protein (GFP), in response to a glioblastoma, the GFP+ cells surrounding the brain tumor were actively dividing (Ki67+), mushashi+, glial precursors (NG2+), GFAP+, PSA-NCAM+ or DCX+. These phenotypes at the lesion site are compatible with the migration of committed and non-committed precursors. Time-lapse experiments showed that among the nestin-GFP+ cells in the SVZ, there were type C cells, GFAP+ cells, neuroblasts, ependymal cells and microglia, where a high percentage of motile nestin-GFP+ cells were DCX−. Taken together, these data suggest that DCX+ neuroblasts do not represent the only motile SVZ-derived cells in the postnatal mouse brain. In cortical injuries, NG2+ cells, Nestin+ GFAP+ cells or SVZ cells able to differentiate into glia were identified in the vicinity of the lesion site at different time points.
Despite years of intensive investigation, the diagnosis and prognosis for most patients with brain tumors or brain lesions remains poor. Median survival for adults with the most common form of brain tumor, the glioblastoma, is 8-12 months. Furthermore, most brain tumors are highly resistant to currently available therapies.
Thus, methods and compositions for prognosis, diagnosis and treatment of brain cancer have been developed which involve the use of antibodies, for instance those disclosed in WO2014186364 or WO2013163431. Specifically, US2013189272 and U.S. Pat. No. 5,558,852 refer to the use of monoclonal antibodies for the diagnosis and treatment of brain cancer. On the other hand, WO8911299 refers to a method for delivery of therapeutic agents to target brain tissue using monoclonal antibody conjugates.
The classification of brain tumors is associated with the cell type from which they arise. Astrocytes, oligodendrocytes, glial cells, may give rise to brain tumors. The presence of markers associated with these cell types may help to define the different tumor types. Neural tumors could derive from early stages of maturation rather than from neural mature cell types. Therefore, the stage at which the tumor is activated must be considered together with the origin of the cell type.
Standard treatment of brain cancer includes surgery, radiotherapy and drug selective chemotherapy. Unfortunately none of these treatments separately or in combinations is effective enough. Actually, high levels of stem cells in the resilient population correlate with a bad prognosis after therapy.
Finally, clinical evidences support the finding that some low-grade astrocytomas become more aggressive, evolving to high-grade tumors. Nevertheless, there are no markers defining this subset of tumors.
Currently there is a convincing cluster of data suggesting that some cancer cells derive from their precursor cells, which normally develop to mature cells to form individual organs.
Recently, a large number of evidence has demonstrated the presence of specific subpopulations of tumor cells directly involved in the initiation and maintenance of tumors. Defined as “cancer stem cells”, their presence inside tumors is a strong indication of the metastatic capacity of a tumor and its aggressiveness. In fact, one of the major evidences of the presence of tumor initiating-cells (TICs) in solid tumors was found in aggressive brain tumors such as glioblastomas (GBM). Glioblastoma belongs to the group of fast-growing glioma tumors, with a severe prognostic and a life expectation no longer than 24 months. There are no alternative therapies described for these tumors. GBM develops from astrocytes/glial cells and is classified as a grade IV astrocytoma. These are the most invasive type of glial tumors, rapidly growing and commonly spreading to nearby brain tissue. Sometimes, they evolve from a low-grade astrocytoma or an oligodendroglioma. GBM is a devastating brain cancer that typically results in death within 15 months after diagnosis.
Today, only sophisticated imaging techniques can pinpoint brain tumors. Diagnostic tools include computed tomography (CT or CAT scan) and magnetic resonance imaging (MRI). Intra-operative MRI also is used during surgery to guide tissue biopsies and tumor removal. Magnetic resonance spectroscopy (MRS) could help to examine the tumor's profile and determine the nature of the lesions seen on the MRI. Positron emission tomography (PET scan) can help to detect recurring brain tumors.
After brain tumor detection on a CT or MRI scan, a neurosurgeon obtains tumor tissue for a biopsy. The pathological analysis of tumor tissue should assign the tumor name and grade, providing answers about the type cell from where the tumor arise, (vg., astrocytomas arise from astrocytes) and to determine the treatment options and information about prognosis. The genetic abnormalities detected (amplification of the EGFR gene (7p12), mutations in the TP53 gene (17p13.1), loss of chromosome 10) vary depending on the nature of the tumor: primary glioblastoma (de novo) or a secondary glioblastoma (developing from a benign astrocytic tumor).
Recently, derivation of in vitro human tumor neurospheres from GBM and other aggressive brain tumors open the possibility to study cancer initiating cells.
Finally, brain tumors are not being precisely defined since there are not accurate biomarkers available. Hence the validation of new markers that allows an early and better diagnostic is a challenge. On the other hand there is not an efficient therapy for high-grade brain tumors. The first-line treatment is usually surgery, either to confirm the diagnosis with a biopsy or to remove as much of the tumor as possible. Complete resection is rarely feasible, since tumor cells usually infiltrate the surrounding brain tissue. Treatment is then completed with radiotherapy targeted at the tumor bed, combined with chemotherapy (nitrosoureas or temozolamide). In terms of survival, the benefits from adjuvant treatments after surgery are significant, although they remain modest. In case of relapse, second-line chemotherapy or reoperation may be performed. Multidisciplinary teams should carry out management of glioblastoma patients with expertise in neuro-oncology within prospective studies aiming to improve patient survival and quality of life. Prognosis is poor, especially in the absence of gross total resection, in older patients and in case of severe neurological deficits.
According to the above, alternative approaches to those currently existing are needed for an early and more accurate identification of brain damages, including tumors. Moreover, a need exists for an effective way to deliver therapeutic agents specifically in the damaged site in order to treat brain injuries. Such site-directed drug delivery systems would allow a reduction in the doses needed of the drug, since they could exert their therapeutic action directly in the damaged zone.